PDF(Pubmed)
Abstract：
Protein post-translational modifications (PTMs) are crucial for cancer cells to adapt to hypoxia; however, the functional significance of lysine crotonylation (Kcr) in hypoxia remains unclear. Herein we report a quantitative proteomics analysis of global crotonylome under normoxia and hypoxia, and demonstrate 128 Kcr site alterations across 101 proteins in MDA-MB231 cells. Specifically, we observe a significant decrease in K131cr, K156cr and K220cr of phosphoglycerate kinase 1 (PGK1) upon hypoxia. Enoyl-CoA hydratase 1 (ECHS1) is upregulated and interacts with PGK1, leading to the downregulation of PGK1 Kcr under hypoxia. Abolishment of PGK1 Kcr promotes glycolysis and suppresses mitochondrial pyruvate metabolism by activating pyruvate dehydrogenase kinase 1 (PDHK1). A low PGK1 K131cr level is correlated with malignancy and poor prognosis of breast cancer. Our findings show that PGK1 Kcr is a signal in coordinating glycolysis and the tricarboxylic acid (TCA) cycle and may serve as a diagnostic indicator for breast cancer.
摘要：
蛋白质翻译后修饰（PTM）对于癌细胞适应缺氧至关重要；然而，赖氨酸巴豆化（Kcr）在缺氧中的功能意义尚不清楚。在这里，我们报告了在常氧和缺氧下全球巴豆的定量蛋白质组学分析，并证明MDA-MB231细胞中101种蛋白质的128个Kcr位点改变。具体来说,我们观察到K131cr显著下降，缺氧时磷酸甘油酸激酶1(PGK1)的K156cr和K220cr。烯酰辅酶A水合酶1（ECHS1）上调并与PGK1相互作用，导致低氧下PGK1Kcr下调。PGK1Kcr的缺失通过激活丙酮酸脱氢酶激酶1（PDHK1）促进糖酵解并抑制线粒体丙酮酸代谢。低PGK1K131cr水平与乳腺癌的恶性程度和不良预后相关。我们的发现表明，PGK1Kcr是协调糖酵解和三羧酸（TCA）循环的信号，可以作为乳腺癌的诊断指标。
